Associations between inter-individual differences in the pharmacokinetic disposition of an anticancer drug and the efficacy and toxicity of therapy with that agent are well known. The goal of this project is to identify pharmacogenomic determinants of drug exposure and effect, and to utilize the knowledge of these determinants to improve the effectiveness and tolerance of breast cancer therapy. The project brings together a unique mix of researchers with expertise in: clinical care, chemistry, molecular biology, genetics, pharmacometrics, hepatocyte function and biostatistics. The studies of patients with breast cancer will involve both retrospective validations of our previous associations between polymorphisms in genes that control drug metabolism in addition to prospective approaches to addressing this avenue of research. Genetic work will be carried out by investigation of single nucleotide polymorphisms (SNP) in metabolic genes isolated from peripheral blood lymphocytes. In specific Aim 1 we will investigate pharmacogenomics of high-dose cyclophosphamide, cisplatin and carmustine (CPB regimen) in patients with high-risk breast cancer. This study will focus on validating our previously described relationships between polymorphisms, pharmacokinetics and outcome. In addition, we will evaluate polymorphisms which may be related to post-transplant pulmonary toxicity. Specific Aim 2 will entail a prospective study directed at evaluation of the pharmacogenomics of standard-dose doxorubicin + cyclophosphamide (AC). An 1 additional focus of this study will be to attempt development of a means for prediction of myelosuppression following 1 AC therapy. In Specific Aim 3 we will prospectively evaluate the pharmacogenomics of paclitaxel given as a weekly regimen. This study will also have an additional investigation to attempt explanation of inter-patient variability in treatment-related neurotoxicity. Justification for use of these data in a prospective fashion and identification of drug targets for future clinical studies will be provided by conduct of in vitro metabolic studies with anti-breast cancer agents suspected to be involved in polymorphic metabolism as the 4th Aim of this Project. Within the course of this funding period, we intend to translate the work we have outlined in each of the first 3 aims into prospective clinical protocols which use a patient's genetic information to better identify the most appropriate dose and type of anticancer agent for that individual.